5-vitamin D

rarer causes of rickets and osteomalacia

-malabsorption disorders -renal disorders causing decreased synthesis of 1, 25 D3 -phosphate depletion -rare inherited disorders -some genetic variants of the Vitamin D receptors are associated with an accelerated loss of bone minerals with aging and certain familial forms of osteoporosis

consequences of Vit D toxicity

EXTREMELY LETHAL--potent rodenticide! sounds lowkey... children: metastatic calcifications of soft tissues such as kidney adults: bone pain and hypercalcemia but can be used as rodenticide so lowkey scary and bad, don't overdose on vit D supplements kids

vitamin D: plants

dietary sources such as 1. deep-sea fish 2. plants 3. grains contribute the small fraction of required vitamin in plants, vitamin D is present in a precursor form (ergosterol) that is converted to vitamin D3 in the body

describe vitamin D's effect on bone

effects of vitamin D on bone depend on plasma levels of Ca hypocalcemia--> Ca resorption (to get levels back to normal) normocalcemia--> Ca deposition (so that when we absorb more Ca, the levels won't get too high)

factors that regulate 1 alpha hydroxylase

factors that activate 1 alpha-hydroxylase 1. hypocalcemia 2. hypophosphatemia 3. increased PTH levels (primary or secondary from hypocalcemia) factors that inhibit 1 alpha-hydroxylase 1. 1, 25 dihydroxy Vit D (feedback inhibition)

range of Vit D deficiency

for circulating 25 hydroxy Vit D normal reference range: 20-100 ng/mL deficiency: less than 20 ng/mL

who has lower vitamin D production?

individuals with dark skin have a lower level of vitamin D production because of melanin pigmentation

morphology of osteomalacia

interference with bone remodeling--> weak bones--> fractures at areas that bear the most weight (vertebral bodies and femoral necks) 1. since adult bones have formed already rather than getting cartilage overgrowth (rickets in kids), the Vit D deficiency and resulting inability to stimulate osteoblasts to perform bone deposition interferes with bone remodeling 2. there is a ton of unmineralized osteoid matrix that is vulnerable to fractures: especially on vertebral bodies and femoral necks which bear a lot of weight

mechanism during Vit D deficiency

low Vit D--> hypocalcemia--> elevated PTH production which activates Vit D at the expense of losing phosphate 1. Vit D deficiency--hypocalcemia--PTH activated 2. PTH works at... bone: stimulates osteoclast activity--more Ca kidney: activates 1 alpha hydroxylase, stimulates Ca reabsorption and phosphate excretion with FGF23--more Vit D, more Ca, loss of phosphate --the hypophosphatemia created by excessive PTH production and action at kidney impairs the mineralization of bone.

factors that activate 1 alpha-hydroxylase in the kidney to synthesize 1, 25 dihydroxy Vit D

low calcium, low phosphate, increased PTH 1. hypocalcemia directly 2. hypophosphatemia 3. increased PTH levels (primary or secondary from hypocalcemia)

chronic renal failure is bad for which vitamin?

renal failure--low 1 alpha hydroxylase--low 1 alpha, 25 dihydroxy Vit D--low calcium levels

what is a dangerous consequence of Vit D deficiency?

the hypophosphatemia created by excessive PTH production and action at kidney impairs the mineralization of bone.

vitamin D metabolism: kidney

the kidney has 1 alpha hydroxylase to convert 25-OH-D into 1, 25 di-hydroxy vitamin D3 -this is the most potent form of vitamin D in the body that does the functions

what is the most potent form of vitamin D in the body that fulfills its functions?

the kidney has 1 alpha hydroxylase to convert 25-OH-D into 1, 25 di-hydroxy vitamin D3 -this is the most potent form of vitamin D in the body that does the functions

appearance of osteomalacia

unmineralized osteoid--> thickened layer of matrix that stains pink in hematoxylin and eosin preparations -the unmineralized osteoid matrix is arranged around the more basophilic, normally mineralized trabeculae

is a vit D deficiency preventable?

yes, eat a diet high in fish oils

are CYPs involved in the metabolism of any of the vitamins?

yes, the liver has 25 hydroxylase (CYP) to convert vitamin D to 25 hydroxycholecalciferol

how can you get vitamin D toxicity?

just from megadoses of orally administered vit D (not from prolonged exposure to normal sunlight)

causes of Vit D deficiency

limited sun exposure, dietary deficiency. prevent with diet high in fish oil limited sun exposure: -northern latitudes -heavily veiled women dietary deficiency: -children born to mothers who have frequent pregnancies followed by lactation (don't get other nutrients) rare conditions: -malabsorption disorders -renal disorders causing decreased synthesis of 1, 25 D3 -phosphate depletion is another potential cause of rickets -rare inherited disorders

vitamin D: binding to receptor that is closely associated with vitamin A

--1, 25 dihydroxy Vit D binds to a high affinity nuclear receptor (vitamin D receptor) which associates with Vitamin A receptor (RAR and RXR) --therefore, beyond its role on skeletal homeostasis, Vitamin D has immunomodulatory and anti-proliferative effects 1. may help clearance of infection 2. low levels of 1, 25-D3 (so less than 20 ng/dL) is associated with increased incidence of colon, prostate, and breast cancers??

factors that inhibit 1 alpha-hydroxylase in the kidney from synthesizing 1, 25 dihydroxy Vit D

1, 25 dihydroxy Vit D itself in feedback inhibition 1, 25 dihydroxy Vit D (feedback inhibition)

vitamin D metabolism: obtaining vitamin D

1. photochemical synthesis of vitamin D from 7-dehydrocholesterol in the skin 2. absorption of vitamin D from foods and supplements in the gut (deep sea fish, plants via ergosterol, and grains)

sources of vitamin D

1. sunlight (major source): cholecalciferol (vitamin D3) in UVB 2. diet (small fraction): small fraction from deep-sea fish, *plants, and grains -*in plants, a precursor form called ergosterol is converted to Vitamin D3 in the body

vit D: reabsorbs Ca from the distal tubule in the kidney

vit D stimulates calcium reabsorption in the DISTAL tubules of the kidney through another transient receptor

vitamin D functions

maintenance of adequate plasma levels of calcium and phosphorus 1. absorbs Ca from the intestine 2. reabsorbs Ca from the distal tubule in the kidney 3. works with PTH to regulate blood Ca and phosphate through bone resorption/deposition (mineralization) 4. associates closely with Vit A receptor to help with clearance of infections and (maybe reduce cancer risk??!) through the maintenance of adequate plasma levels of calcium and phosphorus, vit D supports 1. metabolic functions 2. normal neuromuscular transmission 3. bone mineralization --1, 25 dihydroxy Vit D binds to a high affinity nuclear receptor (vitamin D receptor) which associates with Vitamin A receptor (RAR and RXR) --therefore, beyond its role on skeletal homeostasis, Vitamin D has immunomodulatory and anti-proliferative effects

vitamin D: sunlight

major source of Vit D is sunlight 1. 7-dehydrocholesterol is a precursor 2. a photochemical reaction that requires solar or artificial UVB converts 7-dehydrocholesterol to cholecalciferol/vitamin D3 individuals with dark skin have a lower level of vitamin D production because of melanin pigmentation when i was 7, i stayed out in the sun all day and got really DEHYDATED/tan.

morphology of rickets

no Vit D--> osteoblasts aren't stimulated to cause Ca deposition during bone development--> overgrowth of cartilage--> weak bendy bones 1. craniotabes: if you press in skull, it will poke in and then snap back out 2. frontal bossing (overproduction of osteoid matrix) 3. rachitic rosary along chest 4. pigeon chest deformity: chest protrudes out (like a pigeon) 5. Harrison groove: protruding abdomen due to inward pull at margin of diaphragm 6. bowing of legs and lumbar lordosis, easy fractures 7. cupping and fraying of metaphysis

vit D: Ca deposition/bone mineralization

normocalcemia--> Ca deposition; mineralization of osteoid matrix and epiphyseal cartilage in both flat and long bones by stimulating osteoblasts to induce the deposition of calcium during bone development flat bones: intramembranous bone formation -mesenchymal cells differentiate directly into osteoblasts -these osteoblasts synthesize the collagenous osteoid matrix that vitamin D will cause the deposition of calcium on long bones: endochondral ossification -growing cartilage at the epiphyseal plates is provisionally mineralized -then, the cartilage is progressively resorbed and replaced by osteoid matrix that is mineralized to create bone

overview of vitamin D metabolism

obtaining vitamin D3, liver step, kidney step 1. vitamin D3 is obtained 2. vitamin D3 binds plasma alpha 1 globulin (D-binding protein/DBP) and is transported to the liver 3. the liver has 25 hydroxylase (CYP) to convert vitamin D to 25 hydroxycholecalciferol 4. the kidney has 1 alpha hydroxylase to convert 25-OH-D into 1, 25 di-hydroxy vitamin D3 -this step has many regulating factors -this step fails in chronic renal failure because you lack 1 alpha hydroxylase -this is the most potent form of vitamin D in the body that does the functions the liver has 25 hydroxylase b/c you must be 25 to drink the kidney is the alpha 1 b/c patel is a nephrologist

vitamin D metabolism: liver

the liver has 25 hydroxylase (CYP) to convert vitamin D to 25 hydroxycholecalciferol

ergosterol

the precursor form of vitamin D found in plants that is converted to vitamin D3 in the body

vit D: absorbs Ca from the intestine

vit D binds to its nuclear receptors to encode a critical calcium transport channel in the duodenum to stimulate intestinal calcium absorption

consequences of vit D deficiency

vit D insufficiency (milder form) -increased risk of bone loss and hip fractures, common in older adults in US and Europe impaired normal neuromuscular transmission -hypocalcemic tetany due to lack of normal neural excitation and the relaxation of muscles impaired bone mineralization -rickets (in children whose epiphyses have not already closed)--> overgrowth of cartilage--> weak bendy bones -osteomalacia (in adults)--> no bone remodeling--> fractures

vit D: works with PTH to regulate blood Ca and phosphate through bone resorption/deposition

vit D works with PTH to REGULATE blood Ca through altering bone resorption/deposition *so keep in mind that Vit D doesn't just resorb bone but can also deposit Ca in states of normalcalcemia 1. vit D maintains calcium and phosphorus at supersaturated levels in the plasma 2. both 1,25-dihydroxy Vit D and PTH induce release of calcium and phosphorus into the circulation effects of vitamin D on bone depend on plasma levels of Ca hypocalcemia--> Ca resorption (to get levels back to normal) normocalcemia--> Ca deposition (so that when we absorb more Ca, the levels won't get too high)